Quantification of Tau Protein Lysine Methylation in Aging and Alzheimer's Disease

Carol J. Huseby, Claire N. Hoffman, Grace L. Cooper, Jean Christophe Cocuron, Ana P. Alonso, Stefani N. Thomas, Austin J. Yang, Jeff Kuret

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Tau is a microtubule-associated protein that normally interacts in monomeric form with the neuronal cytoskeleton. In Alzheimer's disease, however, it aggregates to form the structural component of neurofibrillary lesions. The transformation is controlled in part by age- and disease-associated post-translational modifications. Recently we reported that tau isolated from cognitively normal human brain was methylated on lysine residues, and that high-stoichiometry methylation depressed tau aggregation propensity in vitro. However, whether methylation stoichiometry reached levels needed to influence aggregation propensity in human brain was unknown. Here we address this problem using liquid chromatography-tandem mass spectrometry approaches and human-derived tau samples. Results revealed that lysine methylation was present in soluble tau isolated from cognitively normal elderly cases at multiple sites that only partially overlapped with the distributions reported for cognitively normal middle aged and AD cohorts, and that the quality of methylation shifted from predominantly dimethyl-lysine to monomethyl-lysine with aging and disease. However, bulk mol methylation/mol tau stoichiometries never exceeded 1 mol methyl group/mol tau protein. We conclude that lysine methylation is a physiological post-translational modification of tau protein that changes qualitatively with aging and disease, and that pharmacological elevation of tau methylation may provide a means for protecting against pathological tau aggregation.

Original languageEnglish (US)
Pages (from-to)979-991
Number of pages13
JournalJournal of Alzheimer's Disease
Volume71
Issue number3
DOIs
StatePublished - 2019
Externally publishedYes

Bibliographical note

Funding Information:
We thank Dr. Douglas W. Scharre for access to the Buckeye Brain Bank and Dr. H. Ronald Zielke for access to the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland, Baltimore, MD (contract HHSN275200900011C, Ref. No. N01-HD-9-0011). We also acknowledge the BioAnalytical Facility at the University of North Texas for support of mass spectrometry analyses. This work was supported by grants from the Public Health Service (NS07741 and AG045018). C.N.H. was supported by Molecular Biophysics Training Grant T32 GM118291.

Keywords

  • Aging
  • Alzheimer's disease
  • mass spectrometry
  • methylation
  • phosphorylation
  • post-translational modification
  • tau protein

Fingerprint Dive into the research topics of 'Quantification of Tau Protein Lysine Methylation in Aging and Alzheimer's Disease'. Together they form a unique fingerprint.

Cite this